Microhomology-mediated end joining induces hypermutagenesis at breakpoint junctions

Supriya Sinha, Fuyang Li, Diana Villarreal, Jae Hoon Shim, Suhyeon Yoon, Kyungjae Myung, Eun Shim, Sang Lee

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Microhomology (MH) flanking a DNA double-strand break (DSB) drives chromosomal rearrangements but its role in mutagenesis has not yet been analyzed. Here we determined the mutation frequency of a URA3 reporter gene placed at multiple locations distal to a DSB, which is flanked by different sizes (15-, 18-, or 203-bp) of direct repeat sequences for efficient repair in budding yeast. Induction of a DSB accumulates mutations in the reporter gene situated up to 14-kb distal to the 15-bp MH, but more modestly to those carrying 18- and 203-bp or no homology. Increased mutagenesis in MH-mediated end joining (MMEJ) appears coupled to its slower repair kinetics and the extensive resection occurring at flanking DNA. Chromosomal translocations via MMEJ also elevate mutagenesis of the flanking DNA sequences 7.1 kb distal to the breakpoint junction as compared to those without MH. The results suggest that MMEJ could destabilize genomes by triggering structural alterations and increasing mutation burden.

Original languageEnglish (US)
Article numbere1006714
JournalPLoS Genetics
Volume13
Issue number4
DOIs
StatePublished - Apr 1 2017

Fingerprint

mutagenesis
Mutagenesis
mutation
Reporter Genes
DNA
reporter genes
repair
Genetic Translocation
Mutation
Saccharomycetales
Double-Stranded DNA Breaks
gene
Nucleic Acid Repetitive Sequences
resection
Mutation Rate
homology
translocation
yeast
genome
Genome

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research

Cite this

Microhomology-mediated end joining induces hypermutagenesis at breakpoint junctions. / Sinha, Supriya; Li, Fuyang; Villarreal, Diana; Shim, Jae Hoon; Yoon, Suhyeon; Myung, Kyungjae; Shim, Eun; Lee, Sang.

In: PLoS Genetics, Vol. 13, No. 4, e1006714, 01.04.2017.

Research output: Contribution to journalArticle

Sinha, S, Li, F, Villarreal, D, Shim, JH, Yoon, S, Myung, K, Shim, E & Lee, S 2017, 'Microhomology-mediated end joining induces hypermutagenesis at breakpoint junctions', PLoS Genetics, vol. 13, no. 4, e1006714. https://doi.org/10.1371/journal.pgen.1006714
Sinha, Supriya ; Li, Fuyang ; Villarreal, Diana ; Shim, Jae Hoon ; Yoon, Suhyeon ; Myung, Kyungjae ; Shim, Eun ; Lee, Sang. / Microhomology-mediated end joining induces hypermutagenesis at breakpoint junctions. In: PLoS Genetics. 2017 ; Vol. 13, No. 4.
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